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Gilis, E.

Publications and source records attributed to Gilis, E..

2 recordsLinked to original sources
bioRxiv2025

Optimizing efficacy to safety ratio of glucocorticoids in rheumatoid arthritis models by leveraging PPARα agonism

ObjectivesGlucocorticoids remain essential therapies for several immune- and inflammatory diseases such as rheumatoid arthritis (RA) but are notorious for their (metabolic) side effects. Given the anti-inflammatory and metabolically favorable actions of peroxisome-proliferator activated nuclear receptor (PPAR) agonists, we investigated whether PPAR agonism could enhance the therapeutic efficacy and/or mitigate the (metabolic) side effects of glucocorticoids. MethodsWe evaluated the effects of the synthetic glucocorticoid dexamethasone and the PPAR agonist GW7647 (GW) across three RA model systems: L929sA fibroblasts, primary human fibroblast-like synoviocytes (FLS) and collagen-induced arthritis (CIA) mice. ResultsDexamethasone reduced the inflammatory TNF response in L929sA cells, which was further potentiated by GW. In vivo however, GW reduced the dexamethasone-induced adiposity and hypertriglyceridemia, but not arthritis severity. Curiously, GW alone induced several proinflammatory genes within arthritic synovium which were counteracted by glucocorticoids. Proteomic profiling of TNF-stimulated human FLS revealed that combined use of dexamethasone and GW selectively suppressed interferon-stimulated proteins. In line herewith, co-stimulation with TNF and IFN{beta} amplified the suppressive effect of combined dexamethasone and GW treatment on pro-inflammatory gene expression in L929sA versus TNF alone. ConclusionGW enhances the anti-inflammatory effects of glucocorticoids in human FLS and L929sA, and mitigates metabolic side effects of dexamethasone in vivo, without compromising their efficacy. In addition, PPAR agonism permits to broaden its anti-inflammatory profile to interferon driven pathways. Given that both synthetic glucocorticoids and PPAR agonists are already widely used in (general) clinical practice, these findings offer a promising strategy to optimize glucocorticoid-based therapies. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSO_LISynthetic glucocorticoids such as dexamethasone are widely used as immunosuppressive drugs, but cause many (metabolic) side effects. C_LIO_LIPeroxisome-proliferator-activated nuclear receptor (PPAR) agonists are clinically primarily used to treat symptoms that resemble glucocorticoid-induced side effects, but they also exert (modest) immunosuppressive effects. C_LI What this study addsO_LIThis study explores the therapeutic potential of a combination treatment with dexamethasone and PPAR agonist GW7647 (GW) in cellular and murine models of rheumatoid arthritis C_LIO_LIWe reveal that GW attenuates dexamethasone-induced adiposity and hypertriglyceridemia in vivo, hereby improving glucocorticoid-related side effects. C_LIO_LIThe therapeutic efficacy of dexamethasone is maintained or even enhanced by GW in murine and cellular models of rheumatic arthritis, respectively. C_LIO_LIWe offer novel mechanistic insights in the proposed combination treatment by revealing the selective suppression of interferon signaling pathways in human FLS. C_LI How this study might affect research, practice or policyO_LIGiven that both synthetic glucocorticoids and PPAR agonists are already used in clinical practice, this study offers a promising, translatable strategy to optimize glucocorticoid-based therapies with an improved efficacy/safety ratio. C_LI

immunology↗
bioRxiv2025

Themis and Grb2 form a constitutive structural hub in T cell receptor signalling

Positive selection of thymocytes is essential for laying the foundations of the mammalian immune system that include the T cell repertoire, self-tolerance, and prevention of autoimmunity. Themis, the archetypal member of a metazoan protein family featuring distinctive CABIT domains, crucially regulates thymocyte positive selection by linking signalling by the T cell receptor (TCR) to the linker of activation of TCR (LAT). Intriguingly, Themis has been proposed to function via a constitutive complex with the multifunctional adaptor Grb2. Although poised to represent a paradigm shift in our understanding of TCR signalling, the structural and mechanistic basis of such an assembly has remained enigmatic. Here, we present the cryo-EM structure of Themis in complex with Grb2, which reveals how the tandem CABIT domains of Themis engulf the C-terminal SH3 domain of Grb2 (Grb2SH3C) to enable its latching onto the proline rich sequence of Themis. The remaining two domains of Grb2 adopt at least three conformational poses set to interact with other binding partners such as Sos1. Structural insights from unbound Themis unmask the pronounced flexibility of the CABIT domains of Themis, which becomes ordered upon binding to Grb2 to create a binding hotspot for their constitutive complex. Indeed, Themis variants that abrogate interactions with Grb2 also fail to activate the tyrosine phosphatase SHP-1 after TCR stimulation, analogous to the functional phenotype of Themis-deficient cells. Collectively, our study draws the blueprint of the Themis-Grb2 complex as a dynamic structural hub in T cell development.

immunology↗